Development and Evaluation of Ontogeny Functions of the Major UDP-Glucuronosyltransferase Enzymes to Underwrite Physiologically Based Pharmacokinetic Modeling in Pediatric Populations.

Uridine 5'-diphospho-glucuronosyltransferases (UGTs) demonstrate variable expression in the pediatric population. Thus, understanding of age-dependent maturation of UGTs is critical for accurate pediatric pharmacokinetics (PK) prediction of drugs that are susceptible for glucuronidation. Ontogeny functions of major UGTs have been previously developed and reported.

Xenografted Tumors Share Comparable Fraction Unbound and Can Be Surrogated by Mouse Lung Tissue.

Free (unbound) drug concentration at the site of action is the key determinant of biologic activity since only unbound drugs can exert pharmacological and toxicological effects. Unbound drug concentration in tumors for solid cancers is needed to understand/explain/predict pharmacokinetics, pharmacodynamics, and efficacy relations. Fraction unbound ( ) in tumors is usually determined across several xenografted tumors derived from various cell lines in the drug discovery stage, which is time consuming and a resource burden.

Impact of Sotorasib on the Pharmacokinetics and Pharmacodynamics of Metformin, a MATE1/2K Substrate, in Healthy Subjects.

Background And Objective: The objectives of this study were to evaluate the effect of sotorasib on metformin pharmacokinetics and pharmacodynamics and the effect of metformin on sotorasib pharmacokinetics in healthy subjects. Sotorasib is an oral, small molecule inhibitor of the Kirsten rat sarcoma oncogene homolog (KRAS) G12C mutant protein (KRASG12C) protein approved by the U.S.

Evaluation of levocetirizine in beagle dog and cynomolgus monkey telemetry assays: Defining the no QTc effect profile by timepoint and concentration-QTc analysis.

In prior clinical studies, levocetirizine (LEVO) has demonstrated no effect on ventricular repolarization (QTc intervals), therefore it is a relevant negative control to assess in nonclinical assays to define low proarrhythmic risk. LEVO was tested in beagle dog and cynomolgus monkey (nonhuman primate [NHP]) telemetry models to understand the nonclinical-clinical translation of this negative control. One oral dose of vehicle, LEVO (10 mg/kg/species) or moxifloxacin (MOXI; 30 mg/kg/dog; 80 mg/kg/NHP) was administered to instrumented animals (N = 8/species) using a cross-over dosing design; MOXI was the in-study positive control.

Absorption, metabolism and excretion of [C]-sotorasib in healthy male subjects: characterization of metabolites and a minor albumin-sotorasib conjugate.

Purpose: The objectives of this study were to characterize the absorption, metabolism, and excretion of sotorasib and determine the metabolites present in plasma, urine, and feces in healthy male subjects following a single oral 720 mg dose containing approximately 1 μCi of [C]-sotorasib.

Methods: Urine, feces, and plasma were collected post-dose and assayed for total radioactivity and profiled for sotorasib metabolites. Urine and plasma were also assayed for sotorasib pharmacokinetics.

Absorption, Distribution, Metabolism, and Excretion of [C]-Sotorasib in Rats and Dogs: Interspecies Differences in Absorption, Protein Conjugation and Metabolism.

Sotorasib is a first-in-class, targeted covalent inhibitor of Kirsten rat sarcoma viral oncogene homolog (KRAS) approved by the FDA to treat patients with locally advanced or metastatic non-small cell lung cancer with the KRAS mutation. The mass balance, excretion, and metabolism of [C]-sotorasib was characterized in rats and dogs after a single dose of 60 or 500 mg/kg, respectively. Mean recovery was >90% for both species.

Evaluation of drug-drug interaction potential between omecamtiv mecarbil and rosuvastatin, a BCRP substrate, with a clinical study in healthy subjects and using a physiologically-based pharmacokinetic model.

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure. In vitro, OM is an inhibitor of BCRP. Rosuvastatin, a BCRP substrate, is one of the most commonly prescribed medications in patients with heart failure.

Bronchoalveolar lavage fluid cell subsets associate with the disease course in Löfgren's and non-Löfgren's sarcoidosis patients.

Background: Sarcoidosis is a multisystem granulomatous inflammatory disorder, that predominantly involves the lungs. Patients with Löfgren's syndrome (LS) are characterized by acute onset and usually have the HLA-DRB1*03 (DR3) allele and a good prognosis. Non-LS patients are usually DR3 and are more likely to develop chronic disease.

Nonclinical Safety Profile of Sotorasib, a KRAS-Specific Covalent Inhibitor for the Treatment of -Mutated Cancer.

Sotorasib is a first-in-class KRAS covalent inhibitor in clinical development for the treatment of tumors with the mutation. A comprehensive nonclinical safety assessment package, including secondary/safety pharmacology and toxicology studies, was conducted to support the marketing application for sotorasib. Sotorasib was negative in a battery of genotoxicity assays and negative in an in vitro phototoxicity assay.

Pharmacokinetics, Disposition, and Biotransformation of [C]Omecamtiv Mecarbil in Healthy Male Subjects after a Single Intravenous or Oral Dose.

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator that is currently in clinical development for the treatment of heart failure. The absorption and disposition of [C]OM (60 µCi) were studied after a single intravenous infusion (35 mg over 1 hour) or oral solution dose (35 mg) in 14 healthy male subjects. Mean recovery of the administered [C]OM dose was 85.

Mercapturate pathway metabolites of sotorasib, a covalent inhibitor of KRAS, are associated with renal toxicity in the Sprague Dawley rat.

Sotorasib is a first-in class KRAS covalent inhibitor in clinical development for the treatment of tumors with the KRAS p.G12C mutation. In the nonclinical toxicology studies of sotorasib, the kidney was identified as a target organ of toxicity in the rat but not the dog.

Strain-Dependent Variability of Early Discovery Small Molecule Pharmacokinetics in Mice: Does Strain Matter?

Drug discovery programs routinely perform pharmacokinetic (PK) studies in mice to prioritize lead compounds based on anticipated exposure-efficacy and exposure-toxicity relationships. Because of logistical and/or technical issues, the strain of mouse in early discovery PK studies may not always match the strain in toxicity or efficacy studies. This elicits the question do appreciable strain-dependent differences in PK parameters exist to an extent that would warrant conducting PK studies in a strain that matches efficacy and toxicity models? To understand the impact that strain may have on PK parameters, we selected eight marketed drugs with well characterized absorption, distribution, metabolism, and excretion properties and diverse structures to perform PK studies in three common mouse strains (Bagg Albino c, C57BL/6, and CD-1).

Tobacco smoking induces changes in true DNA methylation, hydroxymethylation and gene expression in bronchoalveolar lavage cells.

Background: While smoking is known to associate with development of multiple diseases, the underlying mechanisms are still poorly understood. Tobacco smoking can modify the chemical integrity of DNA leading to changes in transcriptional activity, partly through an altered epigenetic state. We aimed to investigate the impact of smoking on lung cells collected from bronchoalveolar lavage (BAL).

Enhanced CD8 cytolytic T cell responses in the peripheral circulation of patients with sarcoidosis and non-Löfgren's disease.

Background: The role of CD4 T cells in the immunopathogenesis of pulmonary sarcoidosis is well-established, while less is known about the phenotype and function of CD8 cytolytic T cells (CTLs).

Methods: CD8 CTLs were explored in peripheral blood and bronchoalveolar lavage (BAL) samples obtained from up to 25 patients with sarcoidosis and 25 healthy controls. The proportion of CTLs was assessed by the expression of cytolytic effector molecules perforin, granzyme B and granulysin in CD8 T cells, using flow cytometry.

Humoral immune profiling of mycobacterial antigen recognition in sarcoidosis and Löfgren's syndrome using high-content peptide microarrays.

Introduction: Sarcoidosis is considered an idiopathic granulomatous disease, although similar immunological and clinical features with tuberculosis (TB) suggest mycobacterial involvement in its pathogenesis. High-content peptide microarrays (HCPM) may help to decipher mycobacteria-specific antibody reactivity in sarcoidosis.

Methods: Serum samples from patients with sarcoidosis, Löfgren's syndrome, and TB, as well as from healthy individuals (12/group), were tested on HCPM containing 5964 individual peptides spanning 154 Mycobacterium tuberculosis proteins displayed as 15-amino acid stretches.

Gender differences in the T-cell profiles of the airways in COPD patients associated with clinical phenotypes.

T lymphocytes are believed to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). How T cells are recruited to the lungs and contribute to the inflammatory process is largely unknown. COPD is a heterogeneous disease, and discriminating disease phenotypes based on distinct molecular and cellular pathways may provide new approaches for individualized diagnosis and therapies.

Maximizing the Impact of Physiologically Based Oral Absorption Modeling and Simulation.

The challenge of bringing innovative medicines to patients in combination with intense competition within the pharmaceutical industry has induced companies to develop quality medicines more efficiently and cost-effectively. State-of-the-art approaches to advance drug development have never been so urgent. One such approach that has been gaining traction within the industry is the application of modeling and simulation.

Immune cell activation and cytokine release after stimulation of whole blood with pneumococcal C-polysaccharide and capsular polysaccharides.

Streptococcus pneumonia is a major cause of morbidity and mortality in children and adults worldwide. Lack of fully effective pneumococcal vaccines is a problem. Streptococcus pneumoniae exposes on its surface C-polysaccharide (cell wall polysaccharide, CWPS) and serospecific capsular polysaccharides, used in pneumococcal vaccines.

Distinctive Regulatory T Cells and Altered Cytokine Profile Locally in the Airways of Young Smokers with Normal Lung Function.

Smoking influences the immune system in different ways and, hypothetically, effects on pulmonary effector and regulatory T cells emerge as potentially detrimental. Therefore, we characterized the frequencies and characteristics of CD4+ and CD8+ T cell subsets in the blood and lungs of young tobacco smokers. Bronchoalveolar lavage (BAL) and peripheral blood were obtained from healthy moderate smokers (n = 18; 2-24 pack-years) and never-smokers (n = 15), all with normal lung function.

Approach for Identifying Human Leukocyte Antigen (HLA)-DR Bound Peptides from Scarce Clinical Samples.

Immune-mediated diseases strongly associating with human leukocyte antigen (HLA) alleles are likely linked to specific antigens. These antigens are presented to T cells in the form of peptides bound to HLA molecules on antigen presenting cells, e.g.

T-cell activation and HLA-regulated response to smoking in the deep airways of patients with multiple sclerosis.

Cigarette smoking is a risk factor for multiple sclerosis (MS), and the risk is further multiplied for HLA-DRB1*15(+) smokers. To define the smoke-induced immune responses in the lung we performed bronchoscopy with bronchoalveolar lavage (BAL) on smokers and non-smokers, both MS-patients and healthy volunteers. In the BAL, non-smokers with MS showed an increased preformed CD40L expression in CD4(+) T-cells while smokers displayed an increase in proliferating (Ki-67(+)) T-cells.

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions-an Industry Perspective.

Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (fCL), estimation of fractional contribution of metabolizing enzyme toward metabolism (fm), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify fCL and fm, 2) whether those assessments may be quantitative for certain enzymes (e.

T-cell receptor-HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis.

In pulmonary sarcoidosis, CD4(+) T-cells expressing T-cell receptor Vα2.3 accumulate in the lungs of HLA-DRB1*03(+) patients. To investigate T-cell receptor-HLA-DRB1*03 interactions underlying recognition of hitherto unknown antigens, we performed detailed analyses of T-cell receptor expression on bronchoalveolar lavage fluid CD4(+) T-cells from sarcoidosis patients.

Meta-analysis of hepatic cytochrome P450 ontogeny to underwrite the prediction of pediatric pharmacokinetics using physiologically based pharmacokinetic modeling.

The accurate prediction of pharmacokinetics (PK) is fundamental to underwriting safety and efficacy in pediatric clinical trials; age-dependent PK may be observed with pediatrics because of the growth and maturation processes that occur during development. Understanding the ontogeny of drug-metabolizing enzymes is a critical enabler for pediatric PK prediction, as enzyme expression or activity may change with age. Although ontogeny functions for the cytochrome P450s (CYPs) have been developed, disconnects between ontogeny functions for the same CYP may exist, depending on whether the functions were derived from in vitro or in vivo data.